From Miami: Take the Florida Turnpike south until it ends in Florida City. Continue south on US1 to 80001 Overseas Highway.

From Orlando: Take the Florida Turnpike south to Fort Pierce and continue through Ft. Lauderdale, following signs for Homestead/Key West. Turnpike extension ends at Florida City on US1, which leads to Key Largo. Follow US1 to 80001 Overseas Highway.

From Tampa: Take I-75 south to Naples, and then across Alligator Alley to the Miami Exit and south to the Turnpike extension. Continue south on US1 to 80001 Overseas Highway.